The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review

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1 Gastrointestinal Cancer The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review MICHAEL MICHAEL, a ROCIO GARCIA-CARBONERO, b MATTHIAS M. WEBER, c CATHERINE LOMBARD-BOHAS, d CHRISTOS TOUMPANAKIS, e RODNEY J. HICKS f a Neuorendocrine Service & Division of Cancer Medicine, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Australia; b Hospital Universitario Doce de Octubre, Madrid, Spain; c University Hospital Mainz, Mainz, Germany; d H^opital Edouard-Herriot, Federation des specialites digestives, Lyon, France; e Neuroendocrine Tumour Unit, Royal Free Hospital, London, United Kingdom; f Cancer Imaging & Neuroendocrine Service & Molecular Imaging and Targeted Therapeutics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Australia Disclosures of potential conflicts of interest may be found at the end of this article. Key Words. Lanreotide Neuroendocrine tumors Gastroenteropancreatic neuroendocrine tumors Antiproliferative ABSTRACT Background. Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research. Methods. Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to Results. Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 fulllength publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)- NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET. Conclusion. Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. The Oncologist 2017;22: Implications for Practice: This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease. INTRODUCTION Neuroendocrine tumors (NETs) arise from any cell within the diffuse neuroendocrine system [1], and this gives rise to significant heterogeneity in the characteristics of these tumors and their clinical presentation [2 7]. The most common anatomical sites for NETs are the gastrointestinal (GI) tract and pancreas, which account for >50% of cases, and the pulmonary system [3 13]. In patients with grade 1 (G1) or grade 2 (G2) NETs, the site of the primary tumor is a predictor of outcome [2]. NETs can be characterized as functioning tumors, which secrete hormones and peptides that invoke specific clinical syndromes, or nonfunctioning tumors, which produce nonspecific symptoms related to mass effects and malignancy [3]. Due to delayed diagnosis, many patients with NETs present with inoperable disease; therefore, medical treatment is initiated to control disease progression and to relieve symptoms [14, 15]. Somatostatin is an inhibitory neuropeptide, which acts on various targets throughout the body to regulate a variety of physiological functions, including inhibition of endocrine and Correspondence: Michael Michael, M.D., Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne 3000 Victoria, Australia. Telephone: ; Michael.Michael@petermac.org Received August 9, 2016; accepted for publication September 27, 2016; published Online First on February 20, Oc AlphaMed Press /2016/$20.00/0 The Oncologist 2017;22: Oc AlphaMed Press 2017

2 Michael, Garcia-Carbonero, Weber et al. 273 exocrine secretions as well as the inhibition of normal and tumor cell proliferation. It exerts its effects through interaction with five somatostatin receptor (SSTR) subtypes (SSTR1-5), which belong to the family of G-protein-coupled receptors [16]. Subject to grade, all gastroenteropancreatic (GEP)-NETs can express multiple SSTR subtypes, but SSTR2 generally predominates [17 19]. The predominant expression of SSTR2 on pancreatic or midgut NETs is essential for the control of hormonal hypersecretion by the somatostatin analogs (SSAs). As SSTRs are involved in inhibition of the cell cycle in angiogenesis and induction of apoptosis, SSAs are thought to have antiproliferative, antiangiogenic, and proapoptotic effects [16, 17, 19 24]. Due to the short half-life of native somatostatin, longeracting SSAs such as octreotide LAR (Novartis Pharmaceutical Co., East Hanover, NJ) and lanreotide Autogel (Ipsen, Paris France) are now considered the therapy of choice in controlling symptoms associated with GEP-NETs [25 27], including carcinoid syndrome-related diarrhea and flushing and pancreatic islet cell hormonal-secretory syndromes (i.e., gastrinomas, insulinomas, etc.). A complete or partial clinical response to SSA therapy is generally achieved in at least 50% 90% of patients with carcinoid symptoms [26, 28 32], and biochemical response ranges up to 50% [29]. Reducing serotonin secretion potentially prevents or delays the development of mesenteric fibrosis and carcinoid heart disease, which are related to sustained secretion of this hormone into the splanchnic and hepatic venous systems, respectively [33]. SSAs can also delay tumor growth. This was first demonstrated for octreotide LAR in a small randomized trial in midgut G1 NETs [34]. The subsequent larger randomized CLARINET demonstrated the antiproliferative effects of 120 mg lanreotide Autogel in patients with G1 and G2 midgut NETs and pancreatic NETs (pnets). Other smaller-scale studies have also been conducted in this setting [14]. Guidelines now include recommendations on the first-line use of lanreotide Autogel in patients with G1 or G2 GEP-NETs [35, 36]. The optimal use of lanreotide Autogel in the control of NETs in terms of dosing, timing in relation to local therapies, and its role in combination regimens is unclear. Therefore, to gain a fuller understanding of the evidence and hence identify further areas of research, we conducted a systematic review of the published literature on the antiproliferative efficacy and safety of lanreotide Autogel in the management of NETs. MATERIALS AND METHODS Data and Search Strategy A search in PubMed was conducted up until March 16, 2016 (no start date was specified), and in four congresses (American Society of Clinical Oncology, European Society for Medical Oncology, European Neuroendocrine Tumor Society [ENETS] and North American Neuroendocrine Tumor Society) from 2013 to Key words and Medical Subject Headings terms used during the searches are included in supplemental online Appendix 1. No restriction was made on the type of or publication in the initial searches. Screening and Selection Criteria Identified studies were screened for those reporting efficacy relating to the antiproliferative effect of lanreotide in NETs. Two reviewers reviewed titles, abstracts, and full-length articles. Studies that reported data on lanreotide for the treatment of NETs in human patients and were published in English were included in the review. We included all formulations of lanreotide with the intention of providing the most comprehensive overview of the clinical evidence on lanreotide. The main focus of our discussion of the data is the Autogel formulation, which is currently the most widely studied and available formulation in use, and the only one approved for tumor growth control in the U.S., the European Union, and elsewhere. Outcome Measures The selection of relevant studies focused on clinical trial and case publications; however, selected reviews were included to provide additional information. The outcomes of interest were the antiproliferative efficacy of lanreotide in NETs and its safety and tolerability in studies of its antiproliferative activity. Measures of efficacy included disease markers, tumor response, time to progression (TTP), progression-free survival (PFS), and overall survival (OS). Measures of safety included the frequency of adverse events (AEs), toxicity, and tolerability. RESULTS Description of Included Studies The results from the PubMed database and congress abstract search and screening are presented in Figure 1. The review consisted of 40 publications, including 27 full-length publications [14, 32, 37 61] and 13 congress abstracts (Tables 1 and 2) [62 74]. Thirty-six (90%) of the publications reported on studies performed in Europe, three involved centers in Europe, the U.S., and India (including the two subgroup analyses studies and an open-label extension [OLE] from the core CLARI- NET ), one was performed in the U.S., and one was performed in Israel. Non-Autogel Formulations of Lanreotide The first published record of the use of lanreotide in humans was in 1989 [75]. The focus of the current review is on the evidence-base for lanreotide Autogel, but findings with other formulations are summarized briefly here. In 16 of the 40 selected publications, the formulation of lanreotide was not the Autogel formulation (Table 1) [32, 37, 38, 41 47, 55 60]. The formulations of lanreotide were described as angiopeptin lanreotide (BIM 23014), lanreotide microparticle (MP), and slow- and long-acting lanreotide. Only lanreotide Autogel was referred to in selected congress abstracts. The studies investigating other lanreotide formulations were generally small scale and/or open label or case studies. Overall, these publications showed that other formulations of lanreotide either decreased or normalized the measured disease markers (Table 1). Tumor size was stabilized in up to 70% of treated patients, and objective responses were generally observed in 5% 10% of patients. Antiproliferative Efficacy of Lanreotide Autogel The efficacy of lanreotide Autogel was reported in 24 of the 40 selected publications, involving approximately 913 patients (Table 1). In most publications, the lanreotide Autogel dose examined was 120 mg; however, dosing frequency varied between publications and was either every 4 or 6 weeks. Class I evidence [76] for the antiproliferative effect of lanreotide Oc AlphaMed Press 2017

3 274 Antiproliferative Role of Lanreotide. Figure 1. Record search and screening flow chart. 1, Title and abstracts of all identified records were screened by two reviewers; search terms for records are listed in Appendix 1; 2, identified publications were screened for those reporting efficacy and safety and those relating to the antiproliferative effect of lanreotide; 3, the selection of relevant publications focused on clinical trial and case publications; however, selected reviews were included to provide additional information; 4, publications that reported data on lanreotide for NETs in human patients published in English were included in the review; 5, sixteen of the publications selected were non-autogel formulations of lanreotide. Autogel at a dose of 120 mg every 4 weeks comes from the CLARINET, which was the only randomized, placebocontrolled trial identified [14]. CLARINET was a randomized, double-blind, placebo-controlled, multinational phase III trial that investigated 120 mg lanreotide Autogel versus placebo every 4 weeks for 96 weeks in 204 patients with either well-differentiated or moderately differentiated G1/G2 (Ki-67 index <10%), nonfunctioning, SSTR-positive, GEP-NETs, including pancreas, midgut, or hindgut tumors (Table 1). Patients were observed for weeks before randomization; most patients (96%) did not show disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 during this period. At 24 months, the disease had not progressed in 65.1% (95% confidence interval [CI]: ) of patients who received lanreotide Autogel versus 33.0% (95% CI: ) in the placebo group: a 53% risk reduction [14]. The median PFS in the placebo arm was 18 months but was not reached in the lanreotide arm [14]. Improvements in PFS with lanreotide Autogel were observed in the midgut NET and pnet subgroups, in patients with G1 tumors or G2 tumors, irrespective of whether the hepatic tumor load was >25% or 25%, and in patients of all ages (65 or >65 years of age) and BMI categories [14, 68, 77 79]. In the pnet subgroup of the CLARINET, 37% of patients had a hepatic tumor load >25% and 77% had received no previous treatment for NETs. The median PFS among lanreotide Autogel patients within the pnets subgroup was not reached during the core CLARINET but was 12.1 months in patients receiving placebo [69]. The antitumor efficacy of lanreotide was also confirmed in the CLARINET when assessed according to tumor response using RECIST version 1.0 criteria: 66% of patients in the lanreotide Autogel group and 43% in the placebo group achieved either a partial response or stable disease [80]. The antitumor efficacy of lanreotide was also confirmed in the CLARINET when assessed according to tumor response using RECIST version 1.0 criteria: 66% of patients in the lanreotide Autogel group and 43% in the placebo group achieved either a partial response or stable disease. Although OS did not differ significantly between the placebo and lanreotide Autogel groups, in the CLARINET, the analysis was complicated by crossover from placebo to lanreotide by patients in the placebo group whose disease had progressed or who had completed 96 weeks without progression and continued into the CLARINET OLE [14, 61]. In addition, there was uncertainty over subsequent treatments after disease progression [14]. In CLARINET OLE, patients who had received lanreotide Autogel or placebo in the CLARINET with no disease progression at 96 weeks and patients who had received placebo and had disease progression before 96 weeks could continue Oc AlphaMed Press 2017

4 Michael, Garcia-Carbonero, Weber et al. 275 Table 1. Description of publications included in this review Ref. Country Study design Patients Publications of LAN ATG Studies of 120 mg every 4 weeks Bianchi et al., 2011 [40] Capdevila et al., 2012 [62] Caplin et al., 2014 [14] Caplin et al., 2014 [61] Faggiano et al., 2013 [63] Khan et al., 2011 [49] Lybaert et al., 2014 [50] Italy Multicenter, retrospective Spain Multicenter cohort 12 EU countries, U.S., and India EU, U.S., and India Multinational, randomized, PBO-controlled, phase III OLE (non-randomized) Italy Observational, multicenter Study design Efficacy 23 pts with metastatic WD NETs (GI, pancreas, lung, and unknown) 133 pts with NETs treated with LAN and MTTs (Lung, pancreas, GI, and unknown) 204 pts with WD/MD GEP- NETs (pancreas, midgut, hindgut, and unknown/ other), grade 1/2, disease progression 88 pts from core CLARINET with SD and PBO pts with/without PD. CLARINET : 41 pts received LAN and 47 pts received PBO (pancreas, midgut, hindgut, and unknown/other) 92 pts with GEP-NETs or thoracic NETs France Retrospective 76 pts with metastatic NETs (midgut) Doses of LAN a administered (number of patients or number of doses) LAN ATG 120 mg/4 wks, up to 24 mo LAN ATG 1 1 combination b (115 pts), LAN ATG 1 between 2 (18 pts) and 5 (1 pt) combinations b LAN ATG 120 mg/4 wks (101 pts) or PBO/4 wks (103 pts) for 96 wks or until death/ disease progression. Relevant reported outcomes Disease markers Tumor markers, symptoms, PD, AEs, and treatment feasibility CgA and 5-HIAA levels reduced in 28.6% and 33.3% of GI NETs pts and 75% and 66% of lung NETs pts. Tumor response/ disease progression/ other PR: 8.7% of pts; SD: 65.3% of pts; PD: 26% of pts; median duration of response: 28 mo. PFS, toxicity, and severe AEs NA/NR Probability of PFS at 6, 12, and 18 mo: 89%, 73%, and 67% of pts for LAN 1 sunitinib; 78%, 69%, and 57% of pts for LAN 1 everolimus. Median PFS was not reached. PFS, OS, QoL, and safety NA/NR Prolonged PFS in pts with advanced G1 or G2 (Ki-67 <10%) NETs and SD. PBO versus LAN: prolonged PFS: 18 mo versus not reached; estimate rate of PFS at 24 mo: 65.1% versus 33.0% of pts. LAN ATG 120 mg/4 wks PFS, PD, and safety NA/NR PD in core : 32 pts; median PFS for LAN pts who continued on LAN during OLE: 32.8 mo; TTP for PBO pts in core who switched to LAN in OLE: 14 mo. LAN ATG or OCT LAR SD, PD, tumor response, clinical benefit, clinical, biochemical, and objective tumor response LAN ATG 60 mg/4 wks (23 pts), 90 mg/4 wks (36 pts), 120 mg/4 wks (7 pts); additional treatment c for disease control: 18 pts Belgium Case one pt with pnets (pancreas) OCT LAR 30 mg/4 wks, then LAN ATG 120 mg/4 wks; LAN ATG and chemo initiated after 2 yrs. PFS, clinical or radiological progression, objective response, and tolerance Symptoms, liver tests, and PFS NA/NR Tumor response: 23% of pts; SD: 51% of pts, PD: 26% of pts; clinical, biochemical, and objective response was not significant. 31% and 41% of pts: reduction 50% of pretreatment CgA and 5- HIAA levels, respectively; 48% and 60% of pts any reduction. Radiological and clinical PFS: 93% and 94% at 1 yr, 75% and 70% at 3 yrs, 59% and 45% at 5yrs Sustained symptomatic response: 54% pts (median FU 27 mo); other 46% pts radiological or symptomatic progression at (median FU 42 mo); OS: 96% 1 yr, 78% 3 yrs, 72% 5 yrs. Liver tests were normal PFS for 2 yrs without the need to increase LAN ATG dose. (continued) Oc AlphaMed Press 2017

5 276 Antiproliferative Role of Lanreotide Table 1. (continued) Ref. Country Study design Patients Marconcini et al., 2013 [66] Marconcini et al., 2014 [64] Marconcini et al., 2014 [65] Martın-Richard et al., 2013 [51] Modica et al., 2014 [67] Italy Retrospective Italy Single-center, retrospective Italy Phase II, non-randomized Spain Multicenter, open-label, phase II Italy Retrospective Study design Efficacy 12 pts with WD NETs (lung, pancreas, midgut, appendix, colon and unknown) 22 pts with WD NETs (lung, pancreas, midgut, colon, and unknown) 30 pts WD NETs, with PD (pancreas, GI, lung, and unknown) 30 pts with WD GEP or bronchopulmonary NETs (midgut, stomach, pancreas, and bronchus) 21 pts with NETs of different origins after disease progression under std dose Penke 2014 [54] Germany Case One pt with NETs of testis (testes) Phan et al., 2015 [69] Phan et al., 2015 [68] Raderer et al., 2016 [74] Ramundo et al., 2014 [70] EU, U.S., and India EU, U.S., and India Subgroup analysis of CLARINET Subgroup analysis of CLARINET Germany Single-arm, pilot 91 pts with GEP-NETs (pancreas, midgut, hindgut, and unknown/other) 204 pts with GEP-NETs aged 65 versus >65 (pancreas, midgut, hindgut, and unknown/other) 40 pts with progressive GEP- NETs Italy Perspective 18 pts with duodenopancreatic NETs related to MEN1: 6 pts in group A and 12 pts in group B Ruszniewski et al., 2014 [71] France QoL: results from CLARINET core 204 pts with WD/MD GEP- NETs (pancreas, midgut, hindgut, and unknown/ other), grade 1/2, disease progression Vaslamatzis et al., 2015 [72] Greece Case Two pts (two cases) with pnens (pancreas) Doses of LAN a administered (number of patients or number of doses) First-line: OCT LAR (12 pts); second-line: LAN ATG 120 mg/4 or LAN ATG 60 mg/4 wks IM inj (12 pts). first-line: LAN ATG 120 mg/4 wks, second-line: OCT LAR 30 mg/4 wks (9 pts); or firstline: OCT LAR 30 mg/4 wks, second-line: LAN ATG 120 mg/4 wks (13 pts) Pts received Cape 1,000 mg/ m 2 bid for 1 14 d and SSA (OCT LAR 30 mg/4 wks or LAN LAR 120 mg/4 wks) LAN ATG 120 mg/4 wks (30 pts), 92 wks High dose LAN ATG (6 pts) or OCT LAR (15 pts) Palliative antiproliferative LAN ATG monthly LAN ATG 120 mg/4 wks (42 pts) or PBO/4 wks (49 pts); deep inj. LAN ATG 120 mg/4 wks (101 pts) or PBO/4 wks (103 pts) for 96 wks or until death/ disease progression. LAN ATG 120 mg/4 wks 1 temozolomide for 6 mo followed (if SD) by either LAN ATG 120 mg/4 wks alone or observation LAN ATG 120 mg/4 wks (group A or no treatment [group B]) LAN ATG 120 mg/4 wks (101 pts) or PBO/4 wks (103 pts) for 96 wks or until death/ disease progression. Relevant reported outcomes Disease markers Response rate, tumor progression, AEs, and treatment feasibility Response rate, tumor progression (TTP), AEs, and treatment feasibility Response rate in terms of PFS, AEs, and treatment feasibility PFS, response rate, tumor markers, symptom control, QoL, and safety PFS, tumor response, SD, PD, clinical response/pr, and AEs Tumor response/ disease progression/ other NA/NR First-line OCT, median duration of response: mo; SD: 11; PR: 1. Second-line LAN, median duration of response: mo; SD: 12. Two pts still in treatment. NA/NR First-line, median TTP: mo; SD: 16; PR: 4; PD: 2 Second-line, median TTP: 14.9 mo, SD: 20; PD: 2. NA/NR PFS: 4.9 mo; SD: 54% of pts; PD: 43% of pts; three pts were still in treatment. CgA normalized or decreased by 30% in 70% of pts Median PFS: 12.9 mo; SD: 89% of pts; PD: 7% of pts; complete response: 0 pts; PR: 4% of pts. NA/NR PFS: high dose 32 mo versus std dose 8 mo; SD: 47.5% of pts; PD: 47.5% of pts. SD NA/NR SD achieved. Consistency of treatment effects Consistency of treatment effects: PFS and safety Response according to PR, SD, and PD NA/NR NA/NR NA/NR Effects of LAN on PFS were similar for both age groups. NA/NR After 4 mo of combination, no pts had disease progression (9 SD and 2 PR). Response, SD, and PD NA/NR Group A: 33.3% of pts minor response, 66.7% of pts SD; Group B: 91.7% of pts SD, 8.3% of pts PD. PFS, safety/tolerability, and QoL LAN ATG 120 mg/4 wks Symptoms, disease markers, liver lesion dimensions, and PFS NA/NR LAN PFS versus PBO improved and good safety/tolerability did not affect QoL. Lab test improved Case 1: PFS 10 mo; liver lesions diminished. Case 2: PFS 6 mo lesions diminished in size. (continued) Oc AlphaMed Press 2017

6 Michael, Garcia-Carbonero, Weber et al. 277 Table 1. (continued) Ref. Country Study design Patients Wolin et al., 2015 [79] EU, U.S., and India Studies of doses lower than 120 mg every 4 wks Bajetta et al., 2006 [39] Grozinsky-Glasberg et al., 2008 [48] Palazzo et al., 2013 [52] Panzuto et al., 2006 [53] Publications of non-atg formulations of LAN Antony et al., 1993 [37] Aparicio et al., 2001 [38] Bondanelli et al., 2005 [41] Canobbio et al., 1994 [42] Ducreux et al., 2000 [43] Eriksson et al., 1996 and 1997 [44, 45] Subgroup analysis of CLARINET Italy Multicenter, open-label, phase III Israel Multicenter prospective France Multicenter, retrospective Italy Prospective, single-center Study design Efficacy 204 pts with GEP-NETs in different WHO BMI categories 60 pts with WD NETs (lung, bowel, pancreas, and unknown); low grade of malignancy 15 pts with gastric carcinoid tumors type 1 68 pts with WD digestive NETs, treated with LAN (foregut, midgut, and unknown) 31 pts with WD enteropancreatic NETs (pancreas, intestine, and unknown) U.S. Phase I 27 pts with carcinoid (OCT) or NETs (LAN) (carcinoid, pancreas, and lung) France NA/NR 35 pts with documented metastatic NETs progression (small intestine, pancreas, lung, gall-bladder, and colon) Italy Case One pt with liver metastases of NETs; no evidence of primary tumor (unknown) Doses of LAN a administered (number of patients or number of doses) LAN ATG 120 mg/4 wks (101 pts) or PBO/4 wks (103 pts) for 96 wks or until death/ disease progression 3 injections, LAN ATG 120 mg/6 wks (30 pts); 6 injections, LAN MP 60 mg/3 wks (30 pts) LAN ATG 90 mg (1 pt) or OCT LAR 20/30 mg (14 pts); min. 6mo LAN/3 mo1: LANATG (median dose 90 mg/4 wks) and/or LAN MP (every 2 wks) OCT LAR 30 mg/4 wks or LAN ATG 60 mg/4 wks Escalating dose of OCT IRF from 1.5 mg to 6.0 mg (14 pts). Escalating dose of Angiopeptin LAN from 2.25 mg to 9.0 mg (13 pts) OCT IRF 100 ug/tid (17 pts); IM LAN MP 30 mg/2 wks (11 pts); or combination (7 pts) Relevant reported outcomes Disease markers Tumor response/ disease progression/ other PFS and safety NA/NR Antitumor effects of LAN were similar in all BMI categories. Tumor markers, tumor size, symptoms, safety, and tolerability Safety, tumor disappearance, size and number, and gastrin levels 20.2% decrease in CgA levels with LAN MP and 27.6% with LAN ATG. 10.1% decrease in median 5-HIAA levels with LAN MP, and 29% with LAN ATG Gastrin levels normalized in 25% of pts, and reduced by 80% in 75% of pts. PFS, PD, and tumor control Ki-67 index available 81% of pts, and was up to 5% in 78% of patients. Response rate, SD, safety, survival rate, and PD PR, SD, PD, radiographic changes, carcinoid syndrome symptoms, and safety (AEs, toxicity, and tolerability) Response rate and treatment duration Slow-release LAN for 3 mo Clinical and biochemical signs and tumor size and reduction Italy NA/NR 10 pts with NETs Long-acting LAN Symptoms, disease markers, tumor size, and objective res France Open-label, prospective, phase II Sweden Open-label, pilot, phase II 46 pts with NETs (midgut, foregut, hindgut, liver, lungs, and unknown) 19 pts with advanced, metastatic GI-NETs (foregut, midgut, hindgut, and pancreas) LAN MP 30 mg/2 wks for 6 mo (symptomatic tumors; 30 pts); LAN MP 30 mg/10 d (non-symptomatic tumors; 16 pts) LAN MP 0.75 mg/d, increasing/wk to 12 mg/d after 6 wks and maintained for 12 mo, if tolerated Response rate and duration of SD Tumor size response, SD, and biochemical response rate SD: 64. 3% of LAN MP pts; 67.9% of LAN ATG pts. PD: 32.1% of LAN MP and LAN ATG pts. Complete disappearance: 73% of pts; 20% of pts tumor decreased in size and number. PD: 57.4% of pts; PFS: 29 mo; Tumor control: 50% of pts. NA/NR Response rate: 45.2%; Responders maintained stabilization for 26.5 mo; PD: 54.8% of pts; SD: 45.2% of pts. NA/NR PR: 30.8% of pts, SD: 7.7% of pts; PD: 61.5% of pts; radiographic changes of increased necrosis: 6/8 pts with carcinoid. NA/NR PR: 3% pts; SD: 57% pf pts; median treatment duration: 11 mo. NA/NR Controlled clinical and biochemical signs of tumor; reduction in the diameter of two liver metastases, and disappearance of another lesion, with further reduction after 6 and 18 mo. decrease of 50% 5-HIAA in 5/8 pts No objective response in tumor size. NA/NR Objective response rate: 5%; duration of SD: 9.5 mo in 19 pts. Biochemical tumor markers (5-HIAA, plasma chromogranin reduced at 6 mo and 12 mo (58% of baseline and 68%, respectively) Tumor size response (>50%) in 5% of pts; SD in 70% of pts for 12 mo. Biochemical response rate: 58%. (continued) Oc AlphaMed Press 2017

7 278 Antiproliferative Role of Lanreotide Table 1. (continued) Ref. Country Study design Patients Faiss et al., 1999 [47] Faiss et al., 2003 [46] Raderer et al., 2001 [55] Ricci et al., 2000 [56] Ricci et al., 2000 [57] Rohaizak and Farndon, 2002 [58] Ruszniewski et al., 1996 [59] Tomassetti et al., 1998 [32] Wymenga et al., 1999 [60] Germany NA/NR 30 pts with metastatic GEP- NETs, with PD with SSA (1.5 mg/d) (foregut, midgut, hindgut, and unknown) Germany Prospective, randomized, multicenter trial Study design Efficacy 80 pts with NETs (pancreas, foregut, midgut, hindgut, and unknown) Austria Case One pt with metastatic carcinoid Italy Phase II 15 pts PD with enteropancreatic and midgut NETs (pancreas and midgut) Italy Phase II 25 pts with carcinoid and entero-pancreatic NETs (midgut) UK NA/NR 10 pts with symptomatic non-resectable carcinoid tumors (including midgut and lung) France Prospective, multicenter 39 pts with carcinoid syndrome (gut, bronchi, testes, and unknown) Italy NA/NR 18 pts with GI-NETs (carcinoid tumors, pancreatic, and liver) 5EU countries Prospective, open-label, phase II 55 patients with GI-NETs: 48 with carcinoid tumors; 6 with gastrinoma; 1 with VIPoma (midgut, hindgut, pancreas, liver, and unknown) Doses of LAN a administered (number of patients or number of doses) Ultra high-dose LAN (5 mg tid SC) for 1 year LAN MP 1 mg/tid (25 pts) or IFN-a 5x 106 U/tiw (27 pts), or combination (28 pts) for 12 mo LAN MP 30 mg/10 d, plus interferon-alpha 3 x 5 MU/ week: switched to OCT LAR 20 mg/4 wks LAN MP 30 mg/2 wks for median of 8 mo followed by OCT LAR 20 mg/4 wks, until disease progression LAN MP 20 mg/2 wks until tumor progression Relevant reported outcomes Disease markers Tumor growth and tumorrelated symptoms Serum CgA, serum serotonin, 5-HIAA levels, every 3 mo Tumor response/ disease progression/ other 1 complete and 1 partial remission; SD: 36.7% of pts; PD: 36.7% of pts (3 12 mo). SD and tumor progression NA/NR SD: 19 pts; PD: 14 LAN pts, 15 IFN-a pts, 14 comb pts. Symptoms, SST, and tumor regression Disease markers, objective and biochemical response rate, symptomatic response rate, duration of response, and improvement in PS Objective PR, TS, DS, and biochemical and symptomatic response OCT LAR and LAN MP Response rate and tumor regression LAN MP 30 mg/2 wks, for 6 mo LAN MP 30 mg/10 d for approx. 12 mo LAN MP 30 mg/2 wks, IM for 6mo Symptoms, disease markers, and tumor regression Symptoms, disease markers, and tumor size Hormone-related symptomatology, tumor markers, and tumor size NA/NR LAN: tumoral SST blocked; OCT: tumor regression seen on CT scan. NA/NR Objective PR was 7% of pts, SD 40% of pts, and PD 53% of pts; duration of SD: 7.5 mo; biochemical response rate: 41%; median duration of biochemical response was 5 mo for CR and 7.5 mo for PR; Improvement PS 5/11 pts with PS. NA/NR Objective PR: 8% pts; SD: 40%; median duration of SD: 8.5 mo; biochemical response: 42%; symptomatic response: 70%; median duration of treatment: 10 mo. NA/NR Three pts responded to LAN, three responded to OCT, three responded to both; no tumor regression. 1 mo: 5-HIAA unchanged in 57% of pts, decreased in 18% of pts. 6 mo: 5-HIAA 50% decrease in 42% of pts Reduction in urinary serotonin, 5-HIAA, plasma glucagon, and serum gastrin Markers normalized in 2 pts, reduced in 19 pts, no change in 19 pts, and rose in 5 pts. No signs of tumor regression seen in pts. No significant effects on tumor size were reported. Tumor size: reduced in 2 pts, stable in 25 pts, progression in 4 pts. a In some cases, the exact doses used are undefined. The doses have been included when available. b Combination: LAN ATG 1 sunitinib; LAN ATG 1 everolimus; LAN ATG 1 bevacizumab; LAN ATG 1 sorafenib; LAN ATG 1 pazopanib. c Additional treatment included transarterial hepatic embolization, peptide receptor radionuclide therapy, or interferon or a combination. Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; AE, adverse event; ATG, Autogel; CgA, chromogranin A; Cape, Capecitabine; CR, complete response; CT, computed tomography; d, days; DS, disease stabilization; EU, European Union; FU, follow-up; GEP-NETs, gastroenteropancreatic NETs; GI, gastrointestinal; IFN-a, interferon alpha; IRF, immediate release form; LAN, lanreotide; LAR, long-acting release; MD, moderately differentiated; MEN1, multiple endocrine neoplasia type 1; mo, months; MP, microparticle; MTTs, molecular targeted therapies; MU, million units; NA/NR, not applicable/not reported; NENs, neuroendocrine neoplasms; NETs, neuroendocrine tumors; OCT, octreotide; OLE, open-label extension ; OS, overall survival; PBO, placebo; PD, progressive disease; PFS, progression-free survival; pnens, pancreatic neuroendocrine neoplasms; pnets, pancreatic neuroendocrine tumors; PR, partial response; PS, performance status; pts, patients; QoL, quality of life; SD, stable disease; SSA, somatostatin analogs; SST, somatostatin receptors; std, standard; TS, tumor stabilization; TTP, time to progression; US, United States; VIPoma, Vasoactive intestinal peptide tumor; WD, well-differentiated; wk, week; yr, year. Oc AlphaMed Press 2017

8 Michael, Garcia-Carbonero, Weber et al. 279 Table 2. Safety and tolerability reported in included publications Ref. Albertelli et al., 2016 [73] (ENETS 2016) Anthony et al., 1993 [37] Aparicio et al., 2001 [38] Safety/tolerability Nine SAEs were reported in 7/35 pts with LAN ATG 180 mg/4 wks for 12 mo. Two SAEs were considered treatment-related. TRAEs were minimal and not dose-related. AEs included discomfort at injection sites, mild abdominal cramping during the first week of treatment, and lower extremity edema. One pt developed gallstones after 13 mo of treatment. Three pts discontinued due to side effects. Bajetta et al., 2006 [39] No safety issues identified; no serious/significant AEs related to treatment; AEs (LAN ATG pts, LAN MP pts): abdominal pain (3, 3), diarrhea (4, 2), pyrexia (2, 3), cholelithiasis (2, 0), bronchitis (0, 2), hypertension (0, 2); 25% of pts had glucose values above the normal ranges. Bianchi et al., 2011 [40] No safety issues identified; no severe AEs; 7.4% of pts died; asymptomatic gallstone in 4.3% of pts at baseline and 13% after 24 mo; hyperglycemia in 13% of pts and 17.4% of pts after 24 mo. The satisfactory tolerability of LAN ATG given long period of time. Capdevila et al., 2012 [62] Caplin et al., 2014 [14] Caplin et al., 2014 [61] Canobbio et al., 1994 [42] Ducreux et al., 2000 [43] Eriksson et al., 1996 [44] Eriksson et al., 1997 [45] Faiss et al., 2003 [46] Grozinsky-Glasberg et al., 2008 [48] Khan et al., 2011 [49] Lybaert et al., 2014 [50] Marconcini et al., 2013 [66] (ENETS 2014) Marconcini et al., 2014 [64] (ENETS 2014) Marconcini et al., 2014 [65] (ENETS 2014) Martın-Richard et al., 2013 [51] Modica et al., 2014 [67] (ENETS 2015) Palazzo et al., 2013 [52] Panzuto et al., 2006 [53] Phan et al., 2015 [69] (ASCO GI 2015) Phan et al., 2015 [68] (ASCO GI 2015) Raderer et al., 2016 [74] (ENETS 2016) Ricci et al., 2000 [56] Ricci et al., 2000 [57] Ruszniewski et al., 1996 [59] Ruszniewski et al., 2014 [71] (NANETS 2014) Tomassetti et al., 1998 [32] Wymenga et al., 1999 [60] Vaslamatzis et al., 2015 [72] (ENETS 2015) The reported toxicity was determined by the MTT profile with no significant additional severe AEs related to the combination a with LAN ATG. AEs: 88% of pts; TRAE: 50% of pts; most common TRAE: diarrhea (26% of LAN pts); 6 pts had AEs leading to withdrawal from ; 57 pts had 122 SAEs; No clinically significant trends were observed in other safety assessments. 44% of patients had TRAEs (i.e., after switching to LAN). Most common TRAE: diarrhea (22%). No new safety concerns were identified in the extension. The tolerance was excellent. LAN MP is safe and well tolerated in patients with carcinoid tumors. The treatment was well tolerated with minor AEs. Ten pts completed the and nine pts withdrew after 3 wks to 9 mo, five withdrew due to PD and/or tumor size, and four withdrew due to side effects. AEs were observed. Side effects leading to an interruption of therapy were more frequent in the combination group than in the monotherapy arms. All patients tolerated treatment well (mean FU of 18 months). No SAEs in LAN ATG pts; 4% of pts had increased diarrhea; 4% of pts had asymptomatic cholelithiasis; 6% of pts had mild abdominal pain; 28% of pts with advanced disease died; LAN is a well-tolerated and safe medication. Switched to LAN ATG due to difficulties with the administration of OCT LAR. Pts stopped treatment due to decrease in QoL; pt died 1 mo later. No pts reported any SARs. No pts reported any SARs. Median FU of 50 mo; median OS is not reached (more than half of pts are still alive); G1-G2 toxicities were diarrhea, nausea, and asthenia; G3-G4 toxicities were not reported. 25/30 (83%) pts had 1 AE; 63% of pts with TRAEs; most common TRAEs: diarrhea (40% of pts), asthenia (20% of pts), flatulence (10% of pts), and injection site pain (10% of pts); severe TRAE: one pt with aerophagia; 7% of pts died (nondrug-related); no deterioration in QoL was observed. LAN [also] provided symptom control with stable QoL and a favorable tolerability profile. AEs: abdominal discomfort (5%), asymptomatic gallstone (5%), and type 2 diabetes mellitus (5%). No additional toxicity is observed in high dose compared to std dose. Median FU: 21 mo; No major side effects were noticed. No symptomatic cholelithiasis was noticed. Treatment was stopped in three pts after 7, 15, and 30 mo, respectively, because of diarrhea in two pts and abdominal pain in one pt. No patient had serious side effects that resulted in discontinuation of treatment. Minor side effects (abdominal pain, diarrhea, nausea) developed in 16.1% of patients. Two pts (6.4%) had evidence of gallstones, without symptoms. Three-year survival rate was 100% for 6-mo responders and 52.3% for non-responders. No pts died during FU. The evidence in the pnet subgroup suggesting antitumor effects with LAN [ATG] together with the favorable long-term safety profile support a positive benefit/risk profile for LAN [ATG] as a first-line treatment for pnets. There were no consistent differences in tolerability between age groups. The most common AE was diarrhea irrespective of age and treatment (65 years: LAN [ATG] 36%, PBO 32%; >65 years: LAN [ATG] 33%, PBO 40%). Of 36 patients, 27 patients experienced an AE of G1 and G2, 11 patients developed AE of G3, and one patient developed a SAE. No SAEs were reported; mild side effects were reported in 26% of patients. No significant side effects were reported. LAN [MP] was well tolerated despite transient mild pain or erythema at the injection site in 25% of the pts. Biliary lithiasis appeared in two pts after 6 mo of LAN [MP]. TRAEs occurred in 50% of pts in the LAN [MP] group versus 28% in the PBO group. Gastrointestinal disorders were the most common treatment-related AEs (37% versus 19%). Transient abdominal pain and pain at the injection site reported in two pts, LAN MP suspended due to hypoglycemia in one pt. QoL assessments after 1 mo showed improvements in emotional and cognitive function and diminished fatigue, sleeping disorders, and diarrhea. Eight of 30 assessable patients developed gallstones. No AEs were reported in the two pts. a Combination: LAN 1 sunitinib; LAN 1 everolimus; LAN 1 bevacizumab; LAN 1 sorafenib; LAN 1 pazopanib. Abbreviations: AE, adverse event; ASCO, American Society of Clinical Oncology; ATG, Autogel; FU, follow-up; G1-4, grade 1-4; LAR, long-acting release; mo, month; MP, microparticle; MTT, molecular targeted therapies; NANETS, North American Neuroendocrine Tumor Society; OCT. octreotide; OS, overall survival; PBO, placebo; PD, progressive disease; pnets, neuroendocrine tumors; pts, patients; QoL, quality of life; SAE, serious adverse event; SAR, severe adverse reactions; std, standard; TREA, treatment-related adverse event; wk, week. or switch to 120 mg lanreotide Autogel every 4 weeks [61]. A total of 88 patients participated, 41 continuing on lanreotide Autogel and 47 switched from placebo [61]. Median PFS with lanreotide Autogel was 32.8 months from start of the core for patients who received lanreotide in the core and continued on lanreotide into CLARINET OLE; however, this may represent a highly selected population. Median PFS was 29.7monthsforpatientswithpNETswhoreceivedlanreotide Oc AlphaMed Press 2017

9 280 Antiproliferative Role of Lanreotide Autogel in both the core and the CLARINET OLE studies [69]. The median time to further disease progression was 14.0 months for patients with disease progression and then switching from placebo to lanreotide Autogel [61]. CLARINET is the pivotal demonstrating the antiproliferative effects of lanreotide Autogel in NETs, but other studies are worth discussing (Table 1) [49, 51, 52]. In a multicenter, open-label, phase II Spanish, 30 patients with progressive GEP-NETs or bronchopulmonary NETs received 120 mg lanreotide Autogel every 4 weeks for up to 94 weeks [51]. Progressive disease at baseline was defined as progression according to RECIST version 1.0 in the 6 months before inclusion. A median PFS of 12.9 months was reported. The showed that most patients receiving lanreotide Autogel achieved tumor stabilization (89%) [51]. In a long-term retrospective, 76 patients with metastatic midgut NETs (stable disease in the 11 patients with pretreatment data) and carcinoid syndrome received prolonged release lanreotide Autogel over 9 years at a U.K. center; 69 patients had data available [49]. Initially, 23 patients received 60 mg lanreotide Autogel every 4 weeks, 36 patients received 90 mg every 4 weeks, and 7 patients received 120 mg every 4 weeks. Fourteen patients required an increase in lanreotide dose, from 60 mg or 90 mg to 120 mg every 4 weeks, to control radiological or symptomatic progression [49]. The OS of all patients at 1, 3, and 5 years was 96%, 78%, and 72%, respectively. Radiological PFS at 1, 3, and 5 years was 93%, 75%, and 59%, respectively. In another retrospective conducted at a center in France, 68 patients with well-differentiated digestive NETs were treated with lanreotide Autogel (59 patients), lanreotide MP (6 patients), or both (3 patients). The median dose of lanreotide Autogel was 90 mg every 4 weeks [52]. PFS was significantly longer in patients with low-to-moderate hepatic tumor involvement (25%, PFS >80 months versus 15 months for patients with hepatic tumor involvement >25%, p 5.005) and in patients with stable disease before treatment (>46 months in patients with stable disease before treatment versus 6 months with progressive disease before treatment, p ) [52]. A shorterpfsinpatientswithahigherhepatictumorloadwas also demonstrated in CLARINET [81], but both groups of patients benefited from therapy with lanreotide Autogel. Likewise, primary tumor type (pancreas) was identified as an important prognostic factor determining PFS in CLARINET, but these patients gained benefit from lanreotide Autogel treatment [81]. Combination Therapy Involving Lanreotide Autogel In a Spanish multicenter cohort, 133 patients with NETs were treated with lanreotide Autogel in combination with molecular targeted therapies (MTTs) [62]. The principal reason for combining lanreotide with targeted therapies was to achieve antiproliferative synergy (85% of patients). Data from 159 combined treatments were retrospectively collected to evaluate the safety and efficacy of these combinations. Overall, 115 patients received 1 combination (median duration of treatment was 5.1 months) and 18 patients received between 2 and 5 combinations. The results from this cohort suggested that combining lanreotide with MTTs can enhance efficacy; however, a randomized prospective clinical trial is required. Generally, the safety profile of the combinations in this trial resembled the safety profile of the MTT monotherapy. An Italian phase II, non-randomized trial in 30 patients with progressive, well-differentiated NETs investigated the combination of capecitabine with either lanreotide Autogel or octreotide LAR after the failure of SSAs and/or chemotherapy, everolimus, or Peptide Receptor Radionuclide Therapy (PRRT) [65]. Patients received 1,000 mg capecitabine for 1 14 days and either 120 mg lanreotide Autogel or 30 mg octreotide LAR every 4 weeks until progression. Median PFS was 15.7 months, 4.6 months, and 4.2 months in patients with GI-NET, pnet, and lung NET, respectively, and median OS was not reached after 50 months. No grade 3-4 toxicities were reported. Initial results after 1 year of an ongoing German combining 120 mg lanreotide Autogel every 4 weeks with the oral chemotherapy agent temozolomide for the treatment of advanced progressive GEP-NET suggested no tumor progression in 15 patients after 4 months [74]. More data from this will help elucidate the potential role of this combination. Safety and Tolerability Profile of Lanreotide Autogel Safety and tolerability during studies of antitumor effects in NET patients was reported in 33 of the 40 publications, of which 23 were full-length articles and 11 were congress abstracts (Table 2) [62, 64 69, 71 74]. A large body of evidence also exists from clinical trials and clinical practice on patients with acromegaly or carcinoid syndrome that supports the safety and tolerability of lanreotide Autogel, but this is outside the scope of this review. In most studies included here, safety and tolerability were measured by the incidence of AEs and causes of death. The most frequently reported AEs were abdominal pain, diarrhea, and cholelithiasis. In the CLARINET, similar proportions of AEs were reported in the lanreotide and the placebo groups (88% and 90%,respectively),mostofwhichweremild(17%ineach group) or moderate (44% and 43%, respectively). Treatmentrelated AEs (TRAEs) among patients receiving lanreotide included diarrhea (26/101 patients), abdominal pain (14/101 patients), cholelithiasis (10/101 patients), and hyperglycemia (5/101 patients) [14]. There were no significant differences between treatments for any individual AEs, and no clinically significant trends were seen in the other safety assessments [82]. In the CLARINET OLE patients who continued lanreotide Autogel, the incidences of overall and individual AEs (whether considered treatment-related or not) were generally lower for the OLE compared with the core : for example, the incidence of TRAEs in this group was 57.3% (22/ 41) in the core and 26.8% (11/41) in the OLE [61]. This suggests that no major long-term AEs emerged (up to 72.4 months in CLARINET OLE) with 120 mg lanreotide Autogel. Preliminary results on the safety of higher-dose lanreotide Autogel at an Italian center have been presented [73]. In 35 patients with progressive NET (84% with GEP-NET), 180 mg lanreotide Autogel every 4 weeks for 12 months resulted in two serious TRAEs (cholelithiasis and consequent cholecystitis) [73]. DISCUSSION Antiproliferative Activity of Lanreotide Autogel Lanreotide Autogel at a 120 mg dose has been shown to reduce tumor progression in patients with NETs [14, 43 45, 48, 60]. This review is not a meta-analysis, and no meaningful comparison of median PFS could be made, as median PFS was not Oc AlphaMed Press 2017

10 Michael, Garcia-Carbonero, Weber et al. 281 reported in most studies, tumor response was not assessed in a standardized way, the dose was increased in the course of many studies, and designs and populations varied widely. Despite the large proportion of patients (96%) in the CLARI- NET with no disease progression, according to RECIST version 1.0, in the 3 6 months prior to entry, significant antitumor effects of lanreotide Autogel were observed in all patient subgroups, including those with >25% liver tumor involvement [14, 15]. The results of CLARINET led to the approval of lanreotide Autogel in many countries as an antiproliferative treatment for patients with GEP-NETs. The recommended starting dose is 120 mg lanreotide Autogel every 4 weeks in this setting, but further studies may help determine optimum doses in individual patients. The other SSA that is used for antiproliferative effect in G1 midgut NETs is octreotide. This is based on the PROMID trial, which included patients with G1 midgut NET only [34]. Therefore, although octreotide may have antiproliferative action against pnets or G2 midgut NET (Ki-67 <10%), there is currently no other randomized controlled trial data to confirm the exact extent of the effect in such patients. Although these two SSAs share some common features, their different drug formulations and administered doses mean that care should be taken in assuming that the data on one drug can be extrapolated entirely to the other. This is reflected in current labeled indications for these two SSAs in many countries, which differ in the NET setting, or in some countries such as the U.S., where octreotide is not approved for antiproliferative effects. In the CLARINET trial, patients were recruited only if their tumors were SSTR-positive. Of the five different SSTR subtypes (SSTR1-5), SSTR2 is expressed in approximately 90% of GI-NETs and almost 80% of pnets [83].The actions of the SSAs are mediated mainly through SSTR2 and SSTR5 [84]. There has been some discussion on the effectiveness of lanreotide Autogel or octreotide LAR in the treatment of Octreoscan-negative or SSTR2-negative NETs [84, 85]. The lack of expression of SSTR2 in GEP-NETs treated with lanreotide Autogel or octreotide LAR is a prognostic indicator of the likelihood of tumor recurrence [86, 87]. However, the ENETS 2016 guidelines for the management of intestinal, pancreatic, bronchial, and unknown primary NETs state that SSAs may be considered for the treatment of tumor growth in patients with Octreoscan-negative low tumor burden NETs [36]. SSAs are not recommended for the treatment of Octreoscan-negative G3 NETs that have an aggressive phenotype [88]. Octreoscan has been shown to have suboptimal sensitivity compared to 68 Ga SSA-labeled positron emission tomography (PET) in the detection of small-volume disease [89]. Therefore, increasing adoption of 68 Ga SSA-labeled imaging may facilitate a clearer indication of Octreoscan-negative patients who may benefit from SSAs. Watchful Waiting Versus Early Initiation of Lanreotide Autogel Watchful waiting, until there is evidence of rapid disease progression and/or symptoms develop, has been suggested as an option in patients with nonprogressive low-grade GEP-NETs [35]. The most recent ENETS guidelines suggest watchful waiting as an alternative to an SSA in patients with G1 GEP-NETs with a low tumor burden and stable disease [36]. There appear to be two alternative viewpoints on the role of watchful waiting. Positive results for initiating 120 mg lanreotide Autogel as a first-line antiproliferative treatment in patients with metastatic midgut NETs and pnets are provided by the CLARINET. If the placebo arm of the CLARINET is considered as a surrogate watchful waiting arm, there are clear benefits in terms of significantly greater PFS with lanreotide Autogel [14, 15]. The minor impact of TRAEs associated with lanreotide Autogel, combined with its antiproliferative effects, potentially justifies its early use even in the absence of specific symptoms. Furthermore, many patients with NETs are only diagnosed when nonspecific symptoms trigger further investigations hence treatment to prevent progression is justified. On the other hand, there is limited evidence that withholding treatment with lanreotide Autogel until there is objective evidence of disease progression has an adverse impact on OS, and this supports a watchful waiting approach. Although the CLARINET and CLARINET OLE trials showed improvements in PFS, no difference in OS was observed between treatment arms. This is not entirely unexpected, as the slowly progressive nature of NETs and the effect of other treatments during longterm follow-up make measuring differences in OS between treatments problematic or impractical [90, 91]. Furthermore, the cost impact of introducing a long-acting SSA instead of allowing a period of watchful waiting is unknown, and this should be assessed before recommending treatment for all patients. More studies are needed to determine if the delayed progression (and potentially delaying the worsening of associated symptoms) means that lanreotide Autogel is the best option for all patients with GEP-NETs. In the meantime, clinical judgement and informed patient preference will continue to drive management decisions on an individualized basis for patients with stable or slowly progressing GEP-NET. Measuring Treatment Response in NETs Alternative and more sensitive measures of disease progression ingep-netsmaybeusefulinfuturetrials.intheclarinet, tumor growth was assessed using structural imaging. However, the technique used and, in particular, the timing of contrast enhancement can significantly impact response assessment [92]. Functional imaging with 68 Ga DOTA PET is more sensitive and specific for staging than structural imaging and may be a more appropriate technique for assessing suitability for treatment and response. However, this technique is not globally available or approved at present. Another technique, fluorodeoxyglucose (FDG) PET, has exhibited excellent predictive value for early tumor progression in NET especially as it is a surrogate of more aggressive disease and has prognostic value in metastatic GEP-NETs. FDG PET and SSTR scintigraphy results correlate with PFS and OS in patients with metastatic NETs [93 95]. Chromogranin-A (CgA) and SSTR imaging are the most sensitive indicators of disease burden in NETs. CgA is the most helpful prognostic and diagnostic biomarker, as it is elevated in 90% of patients with metastatic NETs [96]. Lanreotide treatment can achieve normalization of CgA levels in a reasonable proportion of patients with GEP-NET [40], and decreases in the release of CgA are associated with clinical benefits [29, 97]. However CgA can be elevated by several non-net sources, Oc AlphaMed Press 2017

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